In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2771-2771
Abstract:
The evasion of the host's immune system by tumor cells is a well-established mechanism of tumor establishment and progression - a notable example is the upregulation of PD-L1 on tumor cells to inhibit the activation of PD-1-expressing T cells. Identification of this immune escape mechanism has led to numerous therapeutics targeting the PD-1/PD-L1 axis; nevertheless, there remain a significant majority of patients who are unable to benefit from current therapies. Here we present our findings of (i) an active novel immune escape mechanism mediated via OX001R/OX001L receptor-ligand axis, and (ii) an antibody targeting this axis with potential therapeutic benefit. OX001R/OX001L is a newly identified T cell modulatory axis involved in cancer immune escape. The receptor (OX001R) is expressed on activated CD8 T cells and functions as a co-stimulatory molecule. The ligand (OX001L) is expressed on various cancer cells. The downregulation of OX001L is reported to correlate with poorer prognosis and increased risk of metastasis in multiple cancer indications. Our analysis of NSCLC samples showed the degree of tumor T cell infiltration to be significantly correlated with OX001L downregulation (p=0.0001) and PDL1 upregulation, suggesting that the co-stimulatory ligand OX001L may be involved in cancer immune escape. Our further in vitro experiments showed that (i) tumor cells downregulate OX001L and upregulate PDL1 upon T cell engagement and (ii) OX001L downregulation requires direct cell-cell contact and therefore involves a distinct mechanism when compared with the IFN gamma mediated PDL1 upregulation. To apply our discovery to therapeutics, we conducted a series of in vitro and ex vivo assays with agonistic antibodies targeting OX001R. We found that anti-OX001R-specific agonist antibodies promote T cell activation resulting in enhanced IL-2 and IFN gamma production. Moreover, anti-OX001R-specific agonist antibodies efficiently activate patient TILs in ex vivo 3D tumor explants. When tested in a humanized animal model of lung cancer, agonistic anti-OX001R antibody demonstrated significant anti-tumor activity with tumor growth inhibition comparable to that seen with pembrolizumab. Furthermore, additive effect was seen when the combination of anti-OX001R and anti-PD-1 antibodies was tested. Guided by these data, we have developed OXAB1, an agonistic humanized mAb targeting OX001R. The OXAB1 antibody shows enhanced activity in both in vitro and ex vivo studies. Collectively, our results extend the research into cancer immune escape mechanisms associated therapeutics by discovering, and providing evidence of the importance of, the OX001R/OX001L axis; and support the clinical translation of an agonistic antibody to OX001R in cancer therapy, either as monotherapy or in combination with PD-1/PD-L1 blockers. Citation Format: Livija Deban, Wei Cao, Yaoyao Fu, Angelo Kaplan, Rachel L. Duesk, Arnima Bisht, Sudha Swaminathan, San Lin Lou, Manal Amoury, Bukky Adelegan, Joanne Berry, James E. Ackroyd, Chuck Hannum, Robert Boyd, Christian Rohlff, Haining Huang. Harnessing novel immune escape mechanisms for cancer therapeutics: OXAB1 target validation, proof of concept and preclinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2771.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-2771
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
